MPP II - 3.1 PARATHYROID PHYS. & PHARM.

• Plasma calcium levels are tightly regulated by four hormones in humans

Hormones That Increase Plasma Calcium

• Parathyroid hormone (PTH)
• Vitamin D/Calcitriol

Hormones That Decrease Plasma Calcium

• Calcitonin
• FGF23 (Fibroblast Growth Factor 23)

Parathyroid: Calcium Regulation

• A slight decrease in calcium ion concentration in the extracellular fluid causes the parathyroid glands to increase their rate of secretion
• Decreased calcium concentration continues gland hypertrophy

Calcium Absorption: Intestine

• Dietary intake of calcium is around 1 g/day
• Only 15-30% of calcium intake is absorbed in the intestine
• Intestinal absorption occurs via passive and active processes
• Passive absorption occurs via diffusion, especially in the lower small intestine when dietary calcium is abundant
• Active: enters epithelia via apical TRPV channels and is shuttled basolaterally via calbindins
• Actively transported extracellularly by Ca-ATPase. and a Na-Ca antiporter
• This process occurs in the duodenum
• When dietary calcium is low, this is hormonally regulated by Vitamin D

Calcium Absorption: Kidney

• Calcium is filtered by the kidney.
• 99% of filtered calcium is reabsorbed
• Hormonal regulation of calcium occurs
• The mechanism for reabsorption in the distal tubule is active and transcellular, like the same process that occurs in the duodenum

Calcium in the Skeleton

• 99% of total-body calcium is stored in the skeleton
• Two pools of calcium exist within bones:
  • Stable: hydroxyappatite (calcium phosphate), crystals deposited on collagen matrix, only accessible via bone resorption, and it is a slow process
  • Labile: free calcium ions in the bone ECF, which are accessible to buffer swings in plasma calcium and it is a quick process
• PTH and vitamin D regulate Ca2+ and PO4 3-

The Targets of Regulation Include

• Gl tract – absorption
• Kidneys – reabsorption
• Bone - deposition and resorption

Parathyroid Hormone: Function

• It increases circulating Ca2+ by two mechanisms:
• Bone resorption by binding to receptors on the surface of osteoblasts
• Stimulates Ca2+ reabsorption by the renal tubule

Parathyroid Hormone: Regulation

• Parathyroid cells express a specialized GPCR - Ca2+ sensor
• High Ca2+ levels - receptor inhibits PTH secretion

PTH Stimulates Resorption Via

• Binding to receptors on the surface of osteoblasts
  • PTH increases RANKL
  • PTH decreased OPG
• Promotes osteoclastogenesis

Parathyroid Hormone – Altered States

• Hypercalcemia. This is an excess activity of the parathyroid gland
  • Causes rapid release of calcium salts from the bones
  • Depresses nervous system – reflexes slow
  • Lack of appetite and constipation
• Hypocalcemia. This is the hypofunction of the parathyroid glands
  • Low Ca++ ECF concentration causes nervous system excitability
  • Due to increases in neuronal membrane permeability to Na+- causing easy action potential firing.
  • Results in tetany, sometimes seizures

Vitamin D/Calcitriol

• Functionally related to PTH but Structurally very different
• The active form is produced in liver and kidney
• It is hydrophobic and transported in the blood primarily by vitamin D-binding protein
• The primary active vitamin D derivative is 1,25-(OH)2D3, increasing Ca2+ and PO4 3- absorption by the small intestine

Vitamin D/Calcitriol: Synthesis

• 1,25-(OH)2D3 synthesis from vitamin D2 or D3 involves a multistep process that includes both the liver and the kidney
• The major regulatory enzyme for 1,25-(OH)2D3 synthesis is 25(OH)D1-a-hydroxylase
• Vitamin D3 can be synthesized in the skin by keratinocytes and also come from dietary sources

Vitamin D: Synthesis

• Is a multi-step modification of cholesterol
• Vitamin D3 is produced in skin by UV action on cholesterol
• Calcidiol is synthesized from D3 in the liver by the activity of 25-hydroxylase
• Calcitriol is synthesized from calcidiol in the kindey by activity of 1a-droxylase
• PTH promotes expression of 1a-hydroxylase

Vitamin D: Regulation

• The primary factor that regulates 1,25-VitD is PTH
  • PTH increases the activity of 1-a-hydroxylase and decreases the activity of 24-hydroxylase in the kidney
• This shifts the reactions toward the production of 1,25-VitD
• Hormones like growth hormone, prolactin, and estrogen also increase 1,25-VitD levels

Summary of Control of Calcium lon Concentration

• "First Line of Defense" – Buffering of the exchangeable Ca++ in bone
• "Second Line of Defense" - Hormonal control
  • PTH - VitD
  • Calcitonin

Clinical Connections....Hypoparathyroidism

• Parathyroid glands do not secrete sufficient PTH
• Osteocytic resorption of exchangeable calcium decreases and the osteoclasts become almost totally inactive
• Calcium release from the bones is depressed causing calcium in the body fluids to decrease
• When this low calcium level is reached (hypocalcemia) the usual signs of tetany develop
  • Laryngeal muscles especially sensitive to tetanic spasm

Clinical Connections.... Hypoparathyroidism - Treatment

• PTH is rarely used to treat hypoparathyroidism
• In most patients, extremely large quantities of vitamin D are administered
• Vitamin D/Calcitriol. is the main treatment used for hypoparathyroidism
• Calcitriol will increase both calcium and phosphate
  • Monitor serum values closely
    • If needed oral phosphate binders can be used to address high phosphate
• Thiazides are used as their MOA can lower renal clearance of calcium

Clinical Connections.... Hyperparathyroidism

• Excess PTH Secretion
• Ordinarily caused by a tumor of one of the parathyroid glands
• Primary hyperparathyroidism causes extreme osteoclastic activity in the bones - hypercalcemia
  • Elevates the calcium ion concentration in the ECF
  • Decreases the concentration of phosphate ions because of increased renal excretion of phosphate

Treatments for Hyperparathyroidism

• Primary Hyperpara- parathyroid tumor or hyperplasia
• Secondary Hyperpara- stems from a secondary source
  • CKD
  • Vit D deficiency
  • Crohns disease
  • Celiac disease

Treatments for CKD

• Oral Phosphate Binders
• Calcitriol and its analogues
• Calcimimetics

Secondary Hyperparathyroidism in CKD

• Interplay of:
  • Hyperphosphatemia
  • Increased blood FGF-23 levels
  • Decreased production of VitD
  • Hypocalcemia
• Decreased renal function leads to:
  • Impairment of 1a-hydroxylase
  • Renal tubular function

Treatment of Secondary Hyperparathyroidism in CKD

• Oral Phosphate Binders
• Calcitriol [1,25(OH)2D3] is the dihydroxylated form of vitamin D3
  • Available in oral and intravenous forms
• Calcitriol should not be administered to patients with CKD until hyperphosphatemia has been controlled
  • Could cause increased plasma levels of both calcium and phosphate
• Paricalcitol [19-nor-1,25(OH)2D2] is a synthetic analogue of vitamin D
• Doxercalciferol [1α-(OH)D2] is the 1a-hydroxylated form of vitamin D2; it is 25-hydroxylated to the fully active 1,25-dihydroxy form in the liver
• Both paricalcitol and doxercalciferol may lower plasma PTH levels without significantly raising plasma calcium levels

Calcimimetics

• Modulate the activity of the calcium-sensing receptor on the chief cells
• Because Vit D treatment can lead to unwanted hypercalcemia and hyperphosphatemia, calcimimetics avoid this occurrence
• Cinacalcet is a calcimimetic and was the first to enter the market
  • Mech of action: binds to the CaSR and modulates its activity by increasing the sensitivity to calcium
  • PTH synthesis and secretion are then suppressed